chr4-42963142-A-C

Variant names:

• chr4-42963142-A-C
• rs10213360
• NM_001080476.3:c.627+8A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001080476.3(GRXCR1):​c.627+8A>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.797 in 1,611,240 control chromosomes in the GnomAD database, including 514,029 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.84 (53345 hom., cov: 32)
  • Exomes 𝑓: 0.79 (460684 hom.)
• Consequence: GRXCR1 NM_001080476.3 splice_region, intron
• Scores: Splicing: ADA: 0.00002498
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.679
• Publications: 12 publications found

Genes affected

GRXCR1 (HGNC:31673): (glutaredoxin and cysteine rich domain containing 1) This gene is one of 60 loci associated with autosomal-recessive nonsyndromic hearing impairment. This gene encodes a protein which contains GRX-like domains; these domains play a role in the S-glutathionylation of proteins and may be involved in actin organization in hair cells. [provided by RefSeq, Sep 2010]

GRXCR1 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 25

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 4-42963142-A-C is Benign according to our data. Variant chr4-42963142-A-C is described in ClinVar as Benign. ClinVar VariationId is 43888.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.964 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080476.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRXCR1	NM_001080476.3	MANE Select	c.627+8A>C		splice_region intron	N/A	NP_001073945.1	A8MXD5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRXCR1	ENST00000399770.3	TSL:1 MANE Select	c.627+8A>C		splice_region intron	N/A	ENSP00000382670.2	A8MXD5

Frequencies

GnomAD3 genomes AF: 0.835 AC: 126743 AN: 151738 Hom.: 53279 Cov.: 32

Gnomad AFR AF: 0.914

Gnomad AMI AF: 0.895

Gnomad AMR AF: 0.856

Gnomad ASJ AF: 0.707

Gnomad EAS AF: 0.986

Gnomad SAS AF: 0.715

Gnomad FIN AF: 0.834

Gnomad MID AF: 0.763

Gnomad NFE AF: 0.786

Gnomad OTH AF: 0.823

GnomAD2 exomes AF: 0.813 AC: 202327 AN: 248980 AF XY: 0.799

Gnomad AFR exome AF: 0.917

Gnomad AMR exome AF: 0.898

Gnomad ASJ exome AF: 0.717

Gnomad EAS exome AF: 0.992

Gnomad FIN exome AF: 0.829

Gnomad NFE exome AF: 0.780

Gnomad OTH exome AF: 0.800

GnomAD4 exome AF: 0.793 AC: 1156803 AN: 1459384 Hom.: 460684 Cov.: 44 AF XY: 0.788 AC XY: 572107 AN XY: 726088

African (AFR) AF: 0.920 AC: 30706 AN: 33386

American (AMR) AF: 0.893 AC: 39899 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.718 AC: 18722 AN: 26060

East Asian (EAS) AF: 0.991 AC: 39317 AN: 39690

South Asian (SAS) AF: 0.699 AC: 60255 AN: 86206

European-Finnish (FIN) AF: 0.827 AC: 44160 AN: 53416

Middle Eastern (MID) AF: 0.724 AC: 4162 AN: 5752

European-Non Finnish (NFE) AF: 0.785 AC: 871722 AN: 1109928

Other (OTH) AF: 0.794 AC: 47860 AN: 60264

GnomAD4 genome AF: 0.835 AC: 126870 AN: 151856 Hom.: 53345 Cov.: 32 AF XY: 0.837 AC XY: 62133 AN XY: 74202

African (AFR) AF: 0.914 AC: 37931 AN: 41488

American (AMR) AF: 0.856 AC: 13016 AN: 15206

Ashkenazi Jewish (ASJ) AF: 0.707 AC: 2449 AN: 3464

East Asian (EAS) AF: 0.986 AC: 5078 AN: 5148

South Asian (SAS) AF: 0.715 AC: 3436 AN: 4808

European-Finnish (FIN) AF: 0.834 AC: 8844 AN: 10604

Middle Eastern (MID) AF: 0.769 AC: 226 AN: 294

European-Non Finnish (NFE) AF: 0.786 AC: 53347 AN: 67836

Other (OTH) AF: 0.824 AC: 1727 AN: 2096

Alfa AF: 0.786 Hom.: 38766

Bravo AF: 0.844

Asia WGS AF: 0.852 AC: 2958 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Autosomal recessive nonsyndromic hearing loss 25 (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.43
DANN	Benign	0.62
PhyloP100		-0.68
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000025
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs10213360; hg19: chr4-42965159;